Lung cancer is the leading cause of cancer-related deaths in the U.S. Malignant mesothelioma (MM) is an aggressive, therapy-resistant lung cancer that arises primarily from the mesothelial lining of the pleural and peritoneal cavities. Patients with MM usually present with advanced-stage disease that is often surgically inoperable and refractory to standard chemotherapeutic regimens. A marked increase in MM incidence is predicted in developing countries, where usage of asbestos is increasing at an alarming rate. Thus, new approaches for the prevention and management of this disease are urgently needed. MM is a cancer characterized by recurrent genomic losses that typically occur in combination. Molecular genetic studies of human MMs have uncovered recurrent mutations/deletions of several tumor suppressor genes, particularly CDKN2A (encoding p16INK4A and p14ARF), NF2, and BAP1. Genetically engineered mouse models of MM have demonstrated that haploinsufficiency for Cdkn2a, Nf2, or Bap1 accelerates asbestos-induced MM onset and progression, thereby providing both experimental evidence in support of the pivotal role of these tumor suppressor genes in MM pathogenesis and relevant murine models to facilitate preclinical studies of novel chemopreventive and chemotherapeutic agents. Upon exposure to asbestos, macrophages are recruited to sites of asbestos deposition, indicating that one physiological response to mineral fiber exposure is inflammation. Mice exposed to asbestos exhibit recruitment of activated macrophages to the mesothelium. As a result of increased macrophage accumulation, the nearby mesothelial cells are thought to be exposed to pro-inflammatory cytokines such as IL-1? and TNF?. Interestingly, IL-1? and TNF? can act in concert with asbestos fibers to transform normal mesothelial cells in vitro, suggesting that inflammation may directly contribute to MM development. IL-1? has been shown to increase the proliferative capacity of mesothelial cells in vitro while depletion of activated macrophages in an orthotopic mouse model of MM was found to diminish tumorigenesis. Another cytokine, IL-6, is also potentially a key player in asbestos-induced MM formation as the levels of this proinflammatory cytokine are elevated in asbestos exposed mice. Collectively, these data imply that recruitment of activated macrophages as a result of inflammation contributes to mesothelial proliferation and transformation through release of the cytokines IL-1?, IL-6, and TNF?. Thus, chronic inflammation associated with exposure to asbestos may represent a form of extrinsic cancer-related inflammation and may serve as an early intervention target for the delay or prevention of this cancer. Targeting the immune regulators of asbestos induced inflammatory represent a novel approach to the prevention of this deadly disease.